抗凝血薬の臨床的研究
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概要
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In this observation, the initial dosis of Warfarin sodium was ranged from 5 to 20 mg, and the maintenance dosis from 2.5 to 5 mg pro die ; it is possible to keep the coagulation time within therapeutic limits by means of not so large dosage. Among total observation, there existed only one subject who needed the maintenance dosis more than 5 mg. With due consideration to the individual variation of the susceptibility to anticoagulants, when the coagulation time daily controlled was found within therapeutic range, Warfarin from 10 to 20 mg pro die or of 5 mg for two or three days long was administered as the initial dosis, then the maintenance dosis was used. During the maintenance, the coagulation time was determined at least once a week. It took from five to seven days on an average to control the Quick index between 1.5 and 2.0 and the Owren index between 2.0 and 3.0 with the use of 4 or 5 mg pro die of Warfarin. The initial dosis of phenylindandione was ranged from 50 to 200 mg, and the maintenance dosis from 25 to 50 mg pro die. The intravenous injection of 5000 units of heparin showed the maximal effect from 30 to 60 minutes. The most part of its effect was put out from 3 to 6 hours after the injection. On the other hand, it took from 36 to 38 hours that the maximal effect of phenylindandione or Warfarin came out, so that even if heparin plus phenylindandione or heparin plus Warfarin was administered, it could not be expected to the desirable anticoagulant effect from 4 to 36 hours after the injection. Therefore it was necessary to repeat the intravenous injection of 5000 units of heparin each 4 hours until the effect of phenylindandione appeared. When the oral use was impossible, heparin or Warfarin was used in succession intravenously or intramuscularly, and occasionally by clysma. The Quick value which is increased more rapidly than the Owren by the administration of Warfarin reaches to the maximum within 26 hours; then the Quick value is gradually put out repeating the wave-like increase and decrease. There is no significant time difference between the oral and intravenous use until the effect of Warfarin appears. The Owren value remains unchanged up to 12 hours by the medication of phenylindandione; thereafter the Owren value begins to increase and reaches to its maximum in 35 or 38 hours. The Quick value shows the almost same mode of change. From August 1961 to July 1962, 645 thrombotest and 443 determinations of prothrombin time (the first step method of Quick) were studied. The blood sample preserved in silicon glass tube at the temperature 6℃ did not modify any measurement-value until 5.5 hours after the collection of blood. The blood sample preserved in ordinary glass tube shows a slight diminution of coagulation time about 2.5 hours after the collection of blood, whereas such a blood tends to show a slight prolongation about 5.5 hours thereafter. The activity of the dissolved reagent for thrombotest is said to be constant at the temperature 37℃ for 30 minutes, at the room temperature for 12 hours or at the temperature 6℃ for 3 days, however the coagulation time appears to be prolonged at the temperature 6℃ for 24 hours after the dissolving of reagent. During this observation owing to the derailment of the thrombotest value or prothrombin-time, the dosage of anticoagulants above mentioned was controlled only 14 times. The coagulation time was determined within 1 hour after the sampling pf hood. Glass tube does not produce any large error, but when the determination is performed some time after the sampling of blood, silicon glass tubes are used. The blood sample preserved in silicon glass tube shows hardly any influence upon the value measured at room temperature up to 2.5 hours after the blood collection. The therapeutic range of the Quick index was found from 1.5 to 2.0, and that of the Owren index from 2.0 to 3.0. During the anticoagulant therapy, the recidivation of embolism was seen only in one subject of whom the Quick index was just then found 1.43 (the Quick value 21.8 seconds, control 15.2 seconds). The patient complicated with hemorrhage showed the Quick index more than 2.5 as well as the Owren index more than 3.0. Indifferently from the duration of the treatment, the coagulation time was used to be reduced by the interruption of the anticoagulant therapy ; the coagulation time became equal to or less than the control value about from 78 to 100 hours after the interruption, and tends to increase 130 hours thereafter. Since the combined use of the Quick's first step method and the Owren's thrombotest was adopted as a routine examination and repeated at least once a week, only three cases complicated with hemorrhage of a slight degree were observed. However the induced hemorrhage was not always complicated, even when the Quick index became more than 2.5 or the Owren index more than 3.0. Except for the Quick-and the Owren index, there exist still many factors responsible for the complication of hemorrhage, i.e., the permeability of vascular wall, its fragility and so on. On this occasion, subjects not seldom complain of general malaise which may be considered as a notice to the control of coagulation time during the therapy. Within the therapeutic dosage of phenylindandione and Warfarin above mentioned, allergic reaction, drug exanthema, hepato-renal disturbance and other side effects could not be seen. In normal control the Owren value was found 38.8 seconds and the Quick 12.3 seconds on an average. Whereas the mean Owren was ranged about from 30 to 40 seconds in congestive heart failure and about 40 seconds in auricular fibrillation. The Owren value was prolonged in subjects with the marked hepatic congestion, i.e., ranged from 40 to 60 seconds, and in patients with hepatic disturbance the distribution of the Owren was of a considerably wide fluctuation, i.e., from 30 to 60 seconds. The Quick value showed also the same tendency as the Owren. The cardiac recompensation and the decrease in hepatic congestion tend to normalize the coagulant factors out of order, so that, on such an occasion the administration of anticoagulants becomes again necessary. With due consideration to the relationship between the coagulation time and temperature, the variation of blood coagulation time depending upon that of temperature or season was carefully observed, however there could not be found any definite correlation between them. Those who needed relative large dosis of coumarin for maintenance might have thrombi, because those who suffer from thrombosis are said to be relatively resistent to coumarin. In conclusion, it may be safe to say that with due consideration to a lot of factors influencirig upon the blood coagulation, above all the individual response to anticoagulants must be determined case by case. About the group of angina pectoris, so far as this observation is concerned, with the respect to the improvement or the mortality of angina pectoris there could not be found any definite difference between the control and the group treated with anticoagulants. During the anticoagulant therapy, only one of 13 cases with angina pectoris showed the anterior infarction pattern of a slight degree on ecg. The patients with intermediary coronary syndrome did not develop to the myocardial infarction by anticoagulant therapy, in one case of them neither thrombosis nor embolism could be .seen on autopsy. Anginal pain was improved from 3 to 14 days' use of anticoagulants. The improvement of anginal pain may be in part attributed to the possibility of an influence upon the autonomic nervous system by anticoagulant therapy. About the group of myocardial infarction, so far as this observation is concerned, with respect to the mortality, frequency, of infarction and rehabilitation rate, there could not be any significant difference between the control and the group treated with anticoagulants. Five cases of mitral valvular disease complicated with atrial fibrillation were treated with anticoagulants for 19.5 months; the recidivation of cerebral embolism was seen only in one of them during this treatment. The anticoagulants proved effective to prevent the development of focal symptoms in such subjects as suffering from recurrent attacks of cerebral ischaemia. It appeared also to be possible to prevent the enlargement of focal symptoms as well as the exacerbation of thrombosis, however this treatment is contraindicated when the liquor is bloody or xanthochromic. In pulseless disease (TAKAYASU-SHIMIZU), despite of the frequent attacks of cerebral ischaemia, anticoagulants seemed to be effective to prevent the development of cerebral softning.
- 千葉大学の論文
- 1962-11-28